Nimodipine-loaded mixed micelles: formulation, compatibility, pharmacokinetics, and vascular irritability study

Figures & data

Figure 1 Chemical structure of nimodipine.

Figure 2 Influence of the mass concentration ratio of EPC and SGC on NIM solubilizing efficiency at 25°C (n = 3).

Abbreviations: EPC, egg phosphatidylcholine; SGC, sodium glycocholate; NIM, nimodipine.

Figure 3 Influence of the total concentration of SGC and EPC on NIM solubilizing efficiency at 25°C (n = 3).

Abbreviations: EPC, egg phosphatidylcholine; SGC, sodium glycocholate; NIM, nimodipine.

Table 1 Influence of NIM concentration on the stability of NIMEPC- SGC-MMs

NIM (mg/mL)	EPC + SGC (mg)	Time (h)
		0	1	24	48	72
0.5	40	Y	Y	Y	Y	Y
0.8	40	Y	Y	Y	Y	C
1	40	Y	Y	Y	C	C
1.6	40	C	C	C	C	C
2	40	C	C	C	C	C

Notes: Y = settled solution; C = NIM separating out; n = 3.

Abbreviations: NIM, nimodipine; EPC, egg phosphatidylcholine; SGC, sodium glycocholate; NIM-EPC-SGC-MMs, nimodipine-egg phosphatidylcholine-sodium glycocholate-mixed micelles.

Figure 4 Influence of pH value of dispersed medium on NIM solubilizing efficiency at 25°C (n = 3).

Abbreviation: NIM, nimodipine.

Figure 5 Plot of the fluorescence of pyrene I₁/I₃ intensity ratio versus concentration of EPC/SGC mixed micelles (mass ratio 1:1) in distilled water at 25°C (n = 3).

Abbreviations: EPC, egg phosphatidylcholine; SGC, sodium glycocholate; I₁/I₃, intensity of the third to the first peak (372 and 383 nm) of pyrene.

Table 2 Solubility of NIM-EPC-SGC-MMs

Sample	Solubility (mg/mL)a	Solubilizing efficiencya	Drug loadinga
NIM-EPC-SGC-MMs	0.468 ± 0.009	93.8% ± 2.2%	1.17% ± 0.02%

Notes:

a Reported as means ± standard deviation; n = 3.

Abbreviation: NIM-EPC-SGC-MMs, nimodipine-egg phosphatidylcholine-sodium glycocholate-mixed micelles.

Figure 6 (A) Size and size distribution of the optimal NIM-EPC-SGC-MMs; (B) transmission electron micrograph of NIM-EPC-SGC-MMs (scale bar = 50 nm).

Abbreviation: NIM-EPC-SGC-MMs, nimodipine-egg phosphatidylcholine-sodium glycocholate-mixed micelles.

Table 3 The main pharmacokinetic parameters of the NIM injection and NIM-EPC-SGC-MMs in rats

Parameter	NIM-EPC-SGC-MMs	NIM injection
AUC(0–t) (μg · mL^−1 · min)	434.851 ± 30.886	392.903 ± 34.172
AUC(0–∞) (μg · mL^−1 · min)	461.911 ± 26.984	427.848 ± 23.123
MRT(0–t) (min)	62.722 ± 5.064	61.999 ± 9.887
MRT(0–∞) (min)	83.996 ± 9.373	95.386 ± 37.737
Cmax (μg/mL)	10.214 ± 1.136	9.144 ± 0.797
T1/2z (min)	84.312 ± 6.655	102.394 ± 46.483
CLz (mL · min^−1 · g)	0.004	0.005

Notes: Data reported as means ± standard deviation; n = 5.

Abbreviations: AUC, area under the curve; MRT, mean retention time; NIM-EPCSGC- MMs, nimodipine-egg phosphatidylcholine-sodium glycocholate-mixed micelles.

Figure 7 Mean plasma concentration–time curves of NIM after intravenous injection of NIM injection and NIM-EPC-SGC-MMs in rats (n = 5).

Note: Each point represents mean ± standard deviation.

Abbreviations: NIM, nimodipine; NIM-EPC-SGC-MMs, nimodipine-egg phosphatidylcholine-sodium glycocholate-mixed micelles.

Figure 8 Pathological paraffin sections (hematoxylin-eosin stain) from the ears of rabbits (×100 magnification). (A) Ear sample from rabbit given the NIM injection, showing vasodilation, hemorrhage, and degeneration around and of the vein wall as well as edema around the vein, inflammatory cell infiltration around the vein, and endothelial cell swelling. (B) Ear sample from rabbit given NIM-EPC-SGC-MMs. (C) Ear sample from rabbit given sodium chloride injection. The phenomenon shown in (A) was not observed in (B) or (C).

Abbreviations: NIM, nimodipine; NIM-EPC-SGC-MMs, nimodipine-egg phosphatidylcholine-sodium glycocholate-mixed micelles.